Comorbidities Impact Biomarker Levels to Hinder Alzheimer’s Blood Test Development

New research shows that much more work needs to be done before a simple blood test to diagnose Alzheimer’s disease, perhaps even years before symptoms appear, will be available. The study “Performance of plasma phosphorylated tau 181 and 217 in the community” appears in Nature Medicine.

Two hallmarks of Alzheimer’s disease are tau tangles and beta-amyloid plaques. Tau is a protein found in neurons in the brain. In a healthy brain, tau helps transport nutrients in nerve cells. When an abnormal form of tau builds up, tau tangles are formed. Beta-amyloid plaques are accumulations of brain protein fragments, which can impact cognition.

The interaction of these proteins may speed up brain changes that can lead to Alzheimer’s disease. Tau and beta-amyloid levels can be tested in cerebrospinal fluid, which is retrieved through a lumbar puncture, or through PET imaging of the brain.

“Blood-based biomarkers are the goal in screening for and diagnosing Alzheimer’s disease because they are less costly and invasive, but we need to understand these biomarkers in community-based populations before we use them clinically,” said Michelle Mielke, PhD, professor and chair of epidemiology and prevention at the Wake Forest University School of Medicine and the study’s principal investigator.

Promising new biomarkers

Two blood markers, phosphorylated tau 181 and 217 (p-tau181 and p-tau217), are promising new biomarkers specific to Alzheimer’s disease and may provide a new avenue for screening or detecting Alzheimer’s disease in the general population. However, comorbidities such as chronic kidney disease or history of stroke can also increase these levels and potentially give false positive results, according to Mielke, who added that “Before these blood-based biomarkers enter clinical use, it’s critical that we establish reference ranges and understand the differences age, sex and any underlying health conditions might play.”

“Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30–98 years), in the population-based Mayo Clinic Study of Aging,” write the investigators.

“Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81–0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid.

“The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis, or prognosis at the population level.”

Researchers found that while p-tau181 and p-tau217 increase with age, the increase is mainly among people who are amyloid positive, which provides additional evidence that these biomarkers are specific to Alzheimer’s disease and not other neurodegenerative diseases.

The study’s findings also confirmed that plasma p-tau181 and p-tau217 are predictors of elevated brain amyloid and tau, as measured by PET imaging, but the results were not as good those previously reported in patients seen in specialized memory clinics. A reason for this is that the study showed that multiple comorbidities such as chronic kidney disease, history of myocardial infarction or clinical stroke were also associated with higher plasma p-tau levels.

According to Mielke, this elevation is likely attributed to the underlying conditions and not Alzheimer’s disease and should be considered in the development of cut points for clinical use.

“More research is needed in larger studies, especially in more diverse populations,” Mielke continued. “It’s important for patients and providers to understand that, although these blood markers are very promising, it will take time to implement in the clinic. We need more data first.”